Natural History of NAA15 -Related Neurodevelopmental Disorder Through Adolescence.

The NatA N-terminal acetyltransferase complex is composed of the NAA10 catalytic subunit and the auxiliary subunits NAA15 and HYPK. While those with variants in the enzymatic subunit develop Ogden Syndrome, individuals with variants in the NAA15 coding region develop NAA15-related neurodevelopmental syndrome, which presents with a wide array of manifestations that affect the heart, brain, musculoskeletal system, and behavioral and cognitive development. We tracked a cohort of 27 participants (9 females and 18 males) with pathogenic NAA15 variants over time and administered the Vineland-3 assessment to assess their adaptive functioning. We found that this cohort performed significantly worse compared to the normalized Vineland values. On average, females performed better than males, and they performed significantly better on the motor domain and fine motor sub-domain portions of the assessment. Over time, females showed a significant decrease in adaptive functioning, primarily in the daily living skills and motor domains. Males (after excluding one outlier) showed a moderate positive correlation between age and adaptive behavior composite (ABC) standard score. Despite a similar etiology caused by dysfunction in the NatA complex, NAA15-related neurodevelopmental disorder appears to have a weaker effect on adaptive behavior than Ogden Syndrome. However, these differences are based on comparisons to similar literature, as opposed to head-to-head testing. Lastly, comparisons between probands with loss of function variants in NAA15 and those with missense variants showed no significant differences in adaptive behavior metrics. Ultimately, additional longitudinal data should be collected to determine the validity of the between sex differences and to better understand the change in adaptive behavioral outcomes of individuals with NAA15-neurodevelopmental disorder as they age.